COVID-19 Vaccination Among Patients Receiving Maintenance Renal Replacement Therapy: Immune Response, Real-World Effectiveness, and Implications for the Future

Abstract Chronic kidney disease affects more than 800 million people worldwide and often progresses to end-stage renal disease, which requires maintenance dialysis. Patients receiving dialysis are at higher risk for severe respiratory infections, including SARS-CoV-2 (the causative agent of COVID-19). In addition, many patients who receive dialysis also receive immunosuppressive treatments for conditions such as systemic vasculitis, systemic lupus erythematosus, or malignancies. Many studies have shown that while mRNA COVID-19 vaccines induce some level of immune response in patients receiving dialysis, the magnitude of response is often lower than that of healthy individuals, and responses rapidly wane. Importantly, the risk of COVID-19–related hospitalization and mortality for patients receiving dialysis is 4- to 8-fold higher compared with the general population. In this article, we summarize recent immunogenicity and real-world outcomes of COVID-19 mRNA vaccination among patients receiving dialysis, with a focus on the 3-dose extended primary series and additional (fourth) doses.

Chronic kidney disease (CKD) affects more than 800 million people worldwide and often progresses to end-stage renal disease (ESRD), which requires maintenance dialysis [1,2]. Patients receiving dialysis are at higher risk for severe respiratory infections, including SARS-CoV-2 (the causative agent of , than the general population. This is because of the impaired, rapidly aging immune system of individuals with ESRD. Chronic low-grade inflammation and the high prevalence of comorbidities, such as diabetes and cardiovascular disease, as well as older age, also contribute to the immune system impairment in this population [3][4][5]. In addition, many patients requiring dialysis also receive immunosuppressive treatments for conditions such as systemic vasculitis, systemic lupus erythematosus, or malignancies [6]. Preventive measures such as vaccination remain critical to ensure patients receiving dialysis are protected against diseases; however, successful protection through vaccination can be challenging in these individuals, as the impaired immune responses to infections have also been associated with reduced immune responses to vaccines. Accordingly, it has been noted that individuals who were nonresponders to hepatitis B vaccination [7] are also less likely to have adequate immune responses to COVID-19 vaccines [8,9]. Furthermore, many studies have shown that while mRNA COVID-19 vaccines induce some level of immune response in patients receiving dialysis, the magnitude of responses are often lower than that of healthy individuals and responses rapidly wanes [10,11]. Importantly, the risk of COVID-19-related hospitalization and mortality for patients receiving dialysis is 4-to 8-fold higher compared with the general population [12][13][14]. Given that patients receiving dialysis remain at high risk of severe COVID-19, it is essential that the immune responses and realworld effectiveness of COVID-19 vaccines in this population are well characterized to better inform clinical and public health practices. Initial studies examining 2 doses of mRNA vaccines in patients receiving dialysis have been extensively summarized in several systematic literature reviews and meta-analyses [15][16][17]. In this narrative review, we summarize recent immunogenicity and real-world outcomes of COVID-19 mRNA vaccination among patients receiving dialysis, with a focus on the 3-dose extended primary series and additional (fourth) doses.

Immune Responses to 2 Doses of Vaccine
The phase 2 and 3 clinical studies of mRNA-based COVID-19 vaccines [18,19] did not include patients receiving maintenance dialysis; however, the immunogenicity of 2 doses of mRNA-based vaccines in this population has been characterized in several smaller observational studies. Overall, based on anti-spike (S) immunoglobulin G (IgG) antibody responses, seroresponse rates in patients receiving dialysis following 2 doses of an mRNA vaccine were generally high (92%-98%; Table 1) [9,[20][21][22][23][24][25][26][27]. However, antibody titers were lower in patients receiving dialysis than in the general population [9,20,26]. These findings suggest that early immune responses are generated but are less robust in patients receiving dialysis. In contrast, some studies observed significantly lower seroresponse rates in patients receiving dialysis after 2 doses compared with the general population, including for both SARS-CoV-2 IgG and neutralizing antibodies (82%) [27]. Interestingly, despite an overall response of 94.4% based on SARS-CoV-2specific IgG, a high proportion of patients receiving dialysis had undetectable neutralizing antibodies titers (49% for vaccine-matched SARS-CoV-2 and 77% for the delta variant) [28]. Additionally, varying seropositivity rates have been reported among patients receiving hemodialysis (84.3%) compared with those receiving peritoneal dialysis (92.4%) [17], as well as between patients who received mRNA-1273 (79.8%-97.4%) and those who received BNT162b2 (59.1%-95.7%) [9,[21][22][23]25]. The differences observed in seropositivity among mRNA-1273 and BNT162b2 recipients may be related to differing dosages between these 2 vaccines and/or different study populations or assays. Factors shown to be associated with low antibody titers or lack of seroconversion among patients receiving dialysis include older age, non-Black or non-Native American race, use of immunomodulating medication or anticoagulants, history of transplantation, low serum albumin, and longer length of time on dialysis [9, 22-24, 26, 29, 30]. Cellular immunity is thought to play a key role in disease severity [31]. Lower detectable S-specific T-cell responses (as measured by interferon-ɣ levels) were observed in patients receiving dialysis (46.9%-81.0%) compared with healthy individuals (78.0%-94.6%) after a 2-dose mRNA vaccination regimen [9,20,32]. These numbers vary between patients who received hemodialysis (64%) compared with those who received peritoneal dialysis (80%), similar to the differences observed in humoral responses between patients receiving hemodialysis and peritoneal dialysis [33].
The durability of humoral responses among patients receiving dialysis after 2 doses of an mRNA vaccine has also been examined in several studies [10,11,25]. In a large longitudinal study of 970 patients on dialysis and 125 healthy participants, waning of humoral response for patients receiving dialysis was more pronounced compared with the healthy population, with a respective 68% and 98% of participants maintaining detectable S-specific and receptor binding domain (RBD)-specific IgG antibodies 6 months following vaccination [11]. The decline of antibody titers between 2 and 6 months following vaccination was also faster in patients receiving dialysis (median RBD titers at 2 months, 98.1; at 6 months, 57.7) than healthy individuals (median RBD titers at 2 months, 99.3; at 6 months, 89.0) [11]. In a European study, the factors associated with the faster immunity decline were type of vaccine administered, use of immunosuppressive drugs, male sex, type of dialysis, and length of time on dialysis [11]. Overall, among patients on maintenance dialysis, the magnitude of antibody and T-cell immune responses to 2 doses of mRNA COVID-19 vaccination is lower and immunity wanes faster than in healthy individuals.

Immune Responses to Additional Doses of mRNA COVID-19 Vaccines
A key approach to mitigating the low immune responses and rapid decline after 2 doses of COVID-19 mRNA vaccines has been the administration of additional doses for high-risk populations, including those with CKD and receiving dialysis [34][35][36]. The Advisory Committee on Immunization Practices in the United States now recommends that immunocompromised populations receive a 3-dose primary schedule of mRNA-based vaccines (100-µg dose for mRNA-1273 or 30-µg dose for BNT162b2 [≥12 years of age]) to further boost immune responses [34]. In addition, mix-and-match schedules, wherein a heterologous third dose of an mRNA-based vaccine is administered, may also be used for those who received prior vaccination with a non-mRNA-based vaccine [34].
Compared with responses following dose 2, results from studies characterizing the humoral immune responses to a third dose of mRNA vaccines have shown that this regimen increases SARS-CoV-2 S-specific IgG antibody responses among patients receiving dialysis (Table 2) [3,29,[37][38][39][40][41][42][43][44]. Similar findings were observed among studies evaluating neutralizing antibody responses after 3 doses. Importantly, a study demonstrated that 75% of patients on dialysis with weak or absent (<150 U/mL) antibody responses after 2 mRNA vaccine doses had high (≥150 U/mL) antibody responses to the third dose [45]. Furthermore, a third dose of mRNA vaccine induced a 58.6-fold increase in binding antibody titers and an 18-fold increase in neutralizing antibody titers compared with 2 doses [3,38].
Although administration of a third vaccine dose can improve antibody responses in patients receiving dialysis similar to vaccinated healthy individuals, the durability of responses appears to be limited. In a longitudinal study of patients receiving dialysis, neutralization activity against SARS-CoV-2 declined 3-fold during 121 days of follow-up after a third  [43]. Moreover, a fourth dose has been shown to further seroconvert those who failed to do so after 3 doses [46]. Importantly, a fourth dose of an mRNA vaccine also enhanced neutralizing activity against the omicron variants of concern (from 30%-38% after dose 3 to 64%-80% of participants after dose 4) [43,44], although responses were lower than those against the ancestral strain. Accordingly, updated recommendations in countries such as the United States include a fourth dose of an mRNA vaccine, and more recently, recommendations were further updated to include updated vaccines that include mRNAs encoding for the ancestral SARS-CoV-2 and an omicron variant of concern to broaden protection against SARS-CoV-2 variants [47]. Indeed, in a preliminary study where bivalent vaccination was administered as a fifth dose to patients receiving dialysis, a significant increase in anti-S IgG and neutralization activity was observed against the BA.4 and BA.5 omicron subvariants [48]. However, additional evidence is currently limited for these newer variant-updated vaccines among patients receiving dialysis. Unlike rapid changes in humoral immunity, cellular responses to a third or fourth vaccine dose were more stable over time; the frequency of activated T cells increased slightly after a third or fourth dose and declined moderately over time [43]. Taken together, the administration of additional doses of mRNA vaccine can enhance immune response against SARS-CoV-2 in patients receiving maintenance dialysis.

REAL-WORLD OUTCOMES OF COVID-19 VACCINATION IN PATIENTS RECEIVING DIALYSIS
The authorization of mRNA COVID-19 vaccines and their subsequent worldwide distribution has allowed for rapid accumulation of evidence on real-world outcomes of mRNA vaccines among patients receiving dialysis. In the largest study in the United States to date examining the effectiveness of mRNA COVID-19 vaccination in patients receiving dialysis (January 1 to February 25, 2021), vaccination with a single dose of BNT162b2 (n = 12 169) or mRNA-1273 (n = 23 037) reduced the risk of disease compared with no vaccination (78% and 73% lower relative risk, respectively), COVID-19-related hospitalization (adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], .35-.70 and aOR, 0.68; 95% CI, .51-.91, respectively), and death (aOR, 0.29; 95% CI, .13-.58 and aOR, 0.35; 95% CI, .19-.58, respectively) [49]. Similarly, results from another large retrospective study of 16 213 patients receiving dialysis in the United States (February 2021 to December 2021) indicated that the effectiveness of 2 doses of mRNA vaccine was 45% (mRNA-1273, 50%; BNT162b2, 37%) against COVID-19 infection and 53% against hospitalization or death (mRNA-1273, 63%; BNT162b2, 39%) [50]. However, it remains notable that   [51][52][53]. Interestingly, a meta-analysis study of 7 studies reported a 47% decrease in the risk of COVID-19-related hospital admissions for patients who received 3 doses of mRNA vaccine compared with 2 doses, but no significant differences in the risk of breakthrough infections or all-cause death [54]. Of note, there are currently no published reports on the effectiveness of the bivalent COVID-19 vaccines or the doses beyond the extended 3-dose primary series in patients receiving dialysis. There are also no reports on the effectiveness of the vaccines after January 2022 when the omicron variants became predominant in the population of patients requiring dialysis. In summary, mRNA vaccination improves real-world outcomes stemming from SARS-CoV-2 infection, such as severe disease and death, in patients receiving maintenance dialysis.

CONCLUDING REMARKS
Patients receiving maintenance dialysis remain at higher risk of SARS-CoV-2 infection and severe COVID-19 than healthy individuals [14]. More steps need to be taken to sufficiently protect this population from disease. While optimal COVID-19 vaccination regimens were not investigated for these patients in large clinical trials, a number of smaller prospective and observational studies have been conducted to characterize the immunogenicity elicited by these vaccines in patients receiving dialysis. In this review, we summarized the recent key studies of mRNA COVID-19 vaccines in patients receiving dialysis. Overall, a 2-dose mRNA vaccination regimen induces humoral and cellular immune responses that are lower than those in healthy individuals, with more rapidly waning antibody responses. However, with the subsequent administration of third and fourth doses, antibody responses can be increased. Furthermore, despite lower humoral responses, 2 or more doses of an mRNA-based vaccine can significantly reduce the odds of severe COVID-19, hospitalization, and death in patients receiving dialysis. Protecting vulnerable populations, including those receiving dialysis, has been a primary focus of public health policies throughout the COVID-19 pandemic, with current guidelines in the United States recommending 3 or more doses of mRNA vaccines as the most effective way of preventing serious disease [34]. However, as the COVID-19 pandemic continues to evolve, continued efforts to complement vaccination strategies with early detection and treatments in these populations is essential. Assessing the need for revaccination is warranted and is an approach currently used for hepatitis B vaccination in patients receiving dialysis [55]; however, such monitoring is not performed for COVID-19 due to poorly defined correlates of protection against the omicron variant [34,56]. Other potential strategies for enhancing immune protection against COVID-19 after mRNA vaccination include altering the dose level, timing between doses, or providing alternative routes of vaccine administration; however, the efficacy and safety of these approaches have not yet been studied. In addition to inducing immune protection by vaccination, passive immunity with neutralizing monoclonal antibodies has been used as a treatment approach for COVID-19, although the approach is currently not feasible due to the emergence of new SARS-CoV-2 variants [57]. As such, vaccination strategies have progressed to broaden protection against SARS-CoV-2 variants, such as omicron, by developing variant-updated mRNA vaccines against both the ancestral SARS-CoV-2 and a variant of concern (bivalent vaccines) [58]. These vaccines are now recommended as an additional dose in many countries such as the United States [47]. At the time of this writing, no data have been published on the efficacy and safety of these vaccines among patients receiving dialysis. Potential limitations of the data summarized in this review include the retrospective and observational nature of the studies as well as the underrepresentation of pediatric populations and younger adults, as most studies focused on participants >40 years of age.
In conclusion, this review offers a high-level overview of the immunogenicity and effectiveness of mRNA vaccines in patients receiving dialysis that highlights the benefits of vaccination and identifies the unique challenges in achieving and maintaining immune protection in this population. In the midst of an evolving pandemic, routine surveillance and further studies of the impact of vaccination in patients receiving dialysis are warranted to further characterize immune responses to mRNA-based COVID-19 vaccines as well as those using other platforms. Prompt diagnoses and the availability of treatment options will remain important tools to mitigate the high burden of COVID-19 in this population.

Notes
Acknowledgments. Medical writing and editorial assistance were provided by Agnieszka Looney, PhD, of MEDiSTRAVA in accordance with Good Publication Practice (GPP 2022) guidelines, funded by Moderna, Inc., and under the direction of the authors. Supplement sponsorship. This article appears as part of the supplement "COVID-19 Vaccination in the Immunocompromised Population," sponsored by Moderna, Inc.
Potential conflicts of interest. N. R. received support to her institution from the National Institutes of Health during the development of the present article, received grants or honoraria to her institution from Merck, Sanofi, Pfizer, Quidel, Eli Lilly, and to herself from Krog, Sanofi, and Virology Education, and has participated in a Data Safety Monitoring Board or Advisory Board for ICON, Emmes Company, and Moderna, Inc. M. B.-J. is an employee of Moderna, Inc., and may hold stock or stock options.